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PCSK9 Inhibitors: A Newer Class of Cholesterol Busters

Medically reviewed by L. Anderson, PharmD. Last updated on Dec 20, 2018.

Flashback: A Review of Statins

By now you've heard of statins, also known as HMG-CoA reductase inhibitors. Statins are the cornerstone of treatment to help regulate cholesterol production. Available since the late 1980's, statins include well-known blockbusters like:

Statins work so well because they inhibit an enzyme involved in the making of cholesterol in the liver and boost the number of low density lipoprotein (LDL) receptors to help clear the body of LDL ("bad cholesterol).

However, as researchers have reported, a new class of drugs may change the face of lowering LDL cholesterol. These drugs are known as the PCSK9 Inhibitors.

What Are PCSK9 Inhibitors?

The PCSK9 inhibitors are a class of injectable drugs approved in 2015 that have been shown to dramatically lower LDL cholesterol levels -- by up to 60% in some cases -- when combined with a statin.

PCSK9 inhibitors are monoclonal antibodies (MABs), a type of biologic drug.

  • They bind to and inactivate an enzyme in the liver called proprotein convertase subtilisin kexin 9 (PCSK9).
  • It's important to block PCSK9 because it inactivates the needed receptors on the liver cell surface that transport LDL into the liver for metabolism (break down).
  • Without these receptors, more LDL ("bad" cholesterol) remains in the blood.

So, by inactivating PCSK9, more receptors are available to capture LDL for break down and removal from the blood. And, as we know, lower LDL is better for the heart, and can protect against heart disease, heart attacks and stroke.

Who Needs a PCSK9 Inhibitor?

According to the Centers for Disease Control and Prevention (CDC), about one-third, or 71 million American adults have high levels of low-density lipoprotein (LDL), or “bad,” cholesterol.

  • However, only 1 out of every 3 adults with high LDL is receiving adequate treatment.
  • Less than half of adults with high LDL cholesterol get treatment.
  • In addition, there are about 11 million people who cannot reach their LDL cholesterol goals, even though they have been on a first-line treatment like statins.

In fact, about 1 in 5 patients on statins cannot lower their cholesterol adequately at all; some due to serious genetic defects. In addition, some patients stop their statin treatment due to side effects, like intolerable or dangerous muscle aches, muscle or liver damage, or the development of type 2 diabetes.

PCSK9 inhibitors are used in combination with maximally tolerated doses of statins like atorvasatin or rosuvastatin to further lower the hardest-to-treat elevated cholesterol levels for adult patients with heterozygous familial hypercholesterolemia (HeFH) or heart disease, who require additional lowering of LDL-cholesterol.

Clinical Studies for PCSK9 Inhibitors

Several PCSK9 studies published in the New England Journal of Medicine (NEJM) show that two agents, evolocumab (Repatha) or alirocumab (Praluent), when combined with statins, lower cholesterol better than using just the statin alone.

After one year, those patients who were taking both the PCSK9 inhibitor and the statin together had LDL levels that were at least 60 percent lower than the group taking only statins. LDL levels dropped dramatically.

Larger studies are now available looking at PCSK9 inhibitor ability to lower outcomes like heart attack, stroke, or death, and results suggest cardiovascular events could be significantly lowered by using these medications.

PCSK9 Inhibitors: Administration and Costs

PCSK9 inhibitors are given by subcutaneous (under the skin) injection, via self-administration with a pen device, one or two times per month. In general, PCSK9 inhibitors have been well-tolerated, but the common cold, itching, flu, injection site reactions, and serious allergic reactions have been reported.

Injection site reactions are the most common reaction but infrequently lead to discontinuation of treatment.

Costs:

These drugs are monoclonal antibodies (MABs), large molecule drugs that are usually very expensive.

  • Praluent costs about $14,000 per year (coupon cash price without insurance) in the US.
  • However, Amgen, the manufacturer of Repatha, lowered the price in October 2018 by 60% to $5,850 a year.
  • Individual pricing for patients can be affected by formulary coverage of the drug, rebates, coupons, patient assistance, and insurance type.
  • Contact your insurance company or pharmacist to learn more about how pricing might affect you.

Praluent (alirocumab) by Sanofi/Regeneron

In July 2015, alirocumab (Praluent) by Sanofi and Regeneron was the first PCSK9 inhibitor to receive an FDA-approval. Clinical studies included ODYSSEY, an 18-month, phase 3 trial of 2,341 high-risk patients with high cholesterol on statin therapy. LDL was reduced over 60 percent after 24 weeks, and remained low over 78 weeks.

The incidence of pre-specified cardiac adverse events like heart attack or stroke were lower in the alirocumab group (1.7%) compared to placebo (3.3%), but full cardiovascular outcomes (the effect of Praluent on heart problems such as heart attacks, stroke, or death) were not known yet.

As of December 2018, the product labeling states that the effect of Praluent on cardiovascular morbidity and mortality has not been determined. However, trials on cardiovascular outcomes for alirocumab were published in the NEJM in late November 2018, as noted on the next slide.

Cardiovascular Outcomes with Praluent

Recent trials on cardiovascular outcomes for alirocumab (Praluent) were published in NEJM in November 2018.

Results from the ODYSSEY OUTCOMES trial (Schwartz, et al) with 18,924 patients showed that among patients with a history of acute coronary syndrome 1 to 12 months earlier, the risk of recurrent ischemic cardiovascular events (such as angina, heart attack or stroke) was significantly lower among those who received alirocumab than among those who received placebo. Doses were adjusted to keep LDL levels at 25 to 50 mg per deciliter (mg/dL).

  • Specifically, in patients receiving high-intensity statin therapy, plus either alirocumab or placebo, the primary end point was a composite of death from coronary heart disease, nonfatal myocardial infarction (nonfatal heart attack), fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization.
  • After a follow-up of 2.8 years, the primary end point occurred in 903 patients (9.5%) in the alirocumab group and in 1052 patients (11.1%) in the placebo group, a significant effect. A greater effect was seen in patients with higher LDL (>100 mg/dL) at baseline.
  • However, secondary end points of death from coronary heart disease and death from cardiovascular causes were not found to be significant.
  • Side effects were similar in the two groups, except more local injection-site reactions were seen in the alirocumab group (3.8%) compared to the placebo group (2.1%).

Praluent Side Effects

Praluent (alirocumab) was evaluated in five placebo-controlled trials involving 2,476 patients for the original FDA approval. All patients had HeFH or were otherwise at high risk for heart attack or stroke, and were taking maximally tolerated doses of a statin. Participants taking Praluent had an LDL reduction from 36% to 59% compared to placebo.

The most common side effects have included:

  • nasopharyngitis (common cold)
  • injection site reactions
  • allergic reactions (itching, rash, hives)
  • influenza (flu-like symptoms).

Serious allergic reactions have also been reported: including hypersensitivity vasculitis and hypersensitivity reactions requiring hospitalization.

For a full list of side effects with Praluent, visit here.

Repatha (evolocumab) by Amgen

Repatha (evolocumab) was first FDA-approved in August of 2015.

Repatha injection is used:

  • in adults with cardiovascular (heart) disease to reduce the risk of heart attack, stroke, and certain types of heart surgery.
  • with a cholesterol-lowering diet alone or with diet and other cholesterol-lowering medicines (such as statins or ezetimibe) to treat high blood cholesterol levels known as primary hyperlipidemia (including Heterozygous Familial Hypercholesterolemia ([HeFH]) to reduce low density lipoprotein (LDL), also known as "bad cholesterol".
  • in addition to diet and other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) for the treatment of patients with Homozygous Familial Hypercholesterolemia (HoFH) who require additional lowering of LDL-C.

In Phase 3 clinical trials, Repatha lowered LDL by roughly 60% across all study groups in 12-week and 52-week studies. Repatha reduced LDL cholesterol levels by 61% (from a median of 120 mg/dL to 48 mg/dL over 12 weeks). In HoFH, Repatha reduced LDL by 31%.

Cardiovascular Outcomes with Repatha

In December 2017, the FDA approved additional product labeling for Repatha as the first PCSK9 inhibitor to prevent heart attacks, strokes and coronary revascularizations in adults with established cardiovascular disease.

In the Repatha cardiovascular outcomes study (FOURIER) 27,564 patients who had stable atherosclerotic cardiovascular disease (ASCVD) on statin therapy were evaluated.

Patients who received evolocumab had their LCL-C lowered by 59% to a median of 30 mg/dL.

After a median of 26 months of patient follow-up, Repatha significantly reduced the primary composite endpoint of CV death, MI, stroke, hospitalization for angina, or revascularization (9.8% of patients in the evolocumab group compared to 11.3% of the placebo group). The secondary endpoint of time to first occurrence of cardiovascular death, myocardial infarction, stroke was also significantly reduced from 7.4% to 5.9%.

Repatha significantly reduced the risk of heart attack (27%), stroke (21%), and coronary revascularization (22%). However, as with other trials, there was no effect on time to cardiovascular death.

Side Effects with Repatha

In the OSLER-1 and OSLER-2 open-label studies, side effects occurring with Repatha at a rate of 1% or more included arthralgia (joint pain, 4.6%), injection site reactions (4.3%), headache (3.6%), limb pain (3.3%), and fatigue (2.8%).

Neurocognitive effects like confusion were low (under 1%). Evolocumab treatment was discontinued in 7.2% of 2976 patients. Very low levels of LDL did not appear to affect rates of side effects.

Other side effects include the common cold, upper respiratory tract infections, and injection site reactions. No clinically important drug interactions have been identified with Repatha.

To see a detailed list of side effects visit here.

PCSK9 Dosing

Repatha

The recommended dose of Repatha (evolocumab):

  • 140 mg subcutaneously (under the skin) in the abdomen, thigh, or upper arm every two weeks or 420 mg once monthly for adults with established cardiovascular disease or primary hyperlipidemia (including heterozygous familial hypercholesterolemia).
  • For homozygous familial hypercholesterolemia (HoFH), the approved dose is 420 mg subcutaneously once monthly.

For the 420 mg dose, Repatha can be given:

  • over 9 minutes by using the single-use on-body infusor with prefilled cartridge (Pushtronex System)
  • or by giving 3 injections consecutively within 30 minutes using either the single-use prefilled autoinjector or single-use prefilled syringe.

Praluent

The initial dose of Praluent (alirocumab):

  • 75 mg subcutaneously once every two weeks; most patients will achieve adequate LDL lowering with this dose.
  • If preferred, 300 mg once every 4 weeks (monthly) may be given.

Ongoing PCSK9 Inhibitor Questions

Analysts predict that Repatha and Praluent could each generate annual sales of over $1 billion by 2020, and cardiovascular outcome data that's now available may support this prediction.

But this new drug class could add considerable costs to statin monotherapy -- which primarily exists in a generic and very affordable form now. In fact, a month's supply of generic Lipitor, known as atorvastatin, runs about $8 cash today. However, PCSK9 inhibitor's are meant to treat the highest-risk patients who cannot reach adequate LDL levels with the maximum allowed doses of statins. Usually, these patients have run out of options.

Questions with PCSK9 inhibitors still remain even with the publication of the outcomes data from the Repatha and Praluent trials:

  • What is outcome for the risk of death due specifically to cardiovascular causes, as compared to all-cause death?
  • How will the ODYSSEY OUTCOMES trial change clinical practice with respect to targeting very low LDL levels in high-risk patients? How low should we go?
  • Will these agents find a place in clinical practice for patients who cannot tolerate statins due to severe muscle symptoms?
  • Even with the recent price reduction for Repatha in the U.S., how will the managed care marketplace position this class on their formularies based on cost-effectiveness?
  • Will Sanofi-Aventis and Regeneron lower the price of Praluent, too?

Investigational siRNA Oligonucelotides

In addition to blocking the PCSK9 receptor to lower LDL, blocking the synthesis of PCSK9 can lower LDL levels. Synthesis of PCSK9 requires mRNA. Phase I and II studies have looked at degradation of the mRNA needed for PCSK9 development with a compound called ALN-PCS (inclisiran) from Alnylam Pharmaceuticals/The Medicines Company. Inclisiran is an investigational small interfering ribonucleic acid (siRNA) oligonucelotide that inhibits liver synthesis of PCSK9.

  • In a Phase 2 ORION-1 study, inclisiran lowered PCSK9 and LDL-C levels in high risk patients. Inclisiran can reduce cholesterol by an additional 30 percent to 50 percent on top of statins
  • In Phase I studies, the most common side effects reported were cough, musculoskeletal pain, cold/runny nose, headache, back pain, and diarrhea.
  • Unlike Repatha or Praluent which require 12 or 24 injections per year, this new class may only require 2 or 3 shots yearly. Further studies to investigate effectiveness, safety and long-term use are ongoing.

Bococizumab Studies Halted

In November 2016, Pfizer discontinued the global development of bococizumab, their investigational PCSK inhibitor, as well as the two ongoing cardiovascular outcome studies, SPIRE-1 and SPIRE-2.

Pfizer stated that unexpected results occurred in looking at the outcomes of six Phase III studies. Compared to current agents in this class, LDL lowering over time with bococizumab was not as robust, and a higher level of immunogenicity (antidrug antibodies) and a higher rate of injection-site reactions also occurred.

Due to lack of value to shareholders, especially in the currently marketplace, Pfizer decided to halt the studies worldwide.

Lifestyle is Still an Important Adjunct

Everyone should partake in a healthy lifestyle, whether they have high cholesterol or not. We know you've heard this before, but it really is important:

  • Quit smoking
  • Eat a low fat, low salt diet
  • Exercise 30 to 40 minutes a day on most days of the week
  • Control your stress, learn to relax
  • If you take medications, adhere to your treatment plan and take your medication as directed.

If your cholesterol and LDL levels remains high, even with lifestyle changes, medications to improve your cholesterol might be added to help prevent heart disease and stroke. The statins, PCSK9 inhibitors, and other upcoming investigational agents may offer hope to millions trying to achieve their heart health goals.

Finished: PCSK9 Inhibitors: A Newer Class of Cholesterol Busters

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Sources

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